Cocaine abuse is among the most pressing health/sociological problems confronting developed nations the world over. In the U.S., thousands of new users are added each day and each year a large proportion die from overdose or other toxic influences. The effects on the unborn can be especially tragic. Yet, it is those people addicted to cocaine that represent the financial and social deterioration which this drug can inflict, Significantly, its abuse becomes elevated from the level of the individual as the addict effects not only his own well-being but the health of others and infrastructure of society. Of particular concern is the link between intravenous cocaine administration and the spread of AIDS. At present, there is no concrete medical solution to the cocaine problem. Unlike some other drugs of abuse, there is no pharmacotherapy considered to be of value. The biochemistry of action of cocaine is complex having perhaps the most unique and powerful reinforcing properties of any drug. While a number of potential antagonists, agonists, and anti- depressants have been explored, it has become obvious that alternatives are necessary. One approach might rely on immunological tacts. Such a strategy provides an opportunity to develop pharmacological agents for direct treatment of acute cocaine toxicity and as medications for rehabilitation or preventative purposes. In this way, social programs would be bolstered by an objective scientific foundation. Most exciting, immunological protocols offer the possibility of abating cocaine abuse through vaccine designs. This proposal delineates such an immunopharmacological program. One aspect focuses on monoclonal antibody (mAb) technology derived from both hybridoma and combinatorial library protocols. This encompasses the generation of antibodies which bind cocaine with high affinity and specificity, catalytic antibodies to cleave the benzoyl ester of cocaine, and the elicitation of anti-idiotypes which bear the internal-image of cocaine. The synthesis of new compounds for use as haptens and in ELISA protocols are described. Further, the immunochemistry used for mAb production is applicable to vaccine development via immunoconjugates and anti-idiotypes. The treatment of cocaine toxicity with mAbs and the protection from the effects of cocaine through vaccination will be studied using rat behavioral paradigms. Another feature in the plan is the implementation of molecular biological techniques to alter the structure-function of mAbs. These will be used to enhance mAb binding affinity or introduce catalytic activity. The molecular biology used in the phage-display systems for obtaining mAbs is outlined. In this regard, ground-breaking research has led to the development of synthetic human mAb combinatorial libraries.